The Qualification of an Enrichment Biomarker for Clinical Trials Targeting Early Stages of Parkinson’s Disease

As therapeutic trials target early stages of Parkinson’s disease (PD), appropriate patient selection based purely on clinical criteria poses significant challenges. Members of the Critical Path for Parkinson’s Consortium formally submitted documentation to the European Medicines Agency (EMA) supporting the use of Dopamine Transporter (DAT) neuroimaging in early PD. Regulatory documents included a comprehensive literature review, a proposed analysis plan of both observational and clinical trial data, and an assessment of biomarker reproducibility and reliability. The research plan included longitudinal analysis of the Parkinson Research Examination of CEP-1347 Trial (PRECEPT) and the Parkinson’s Progression Markers Initiative (PPMI) study to estimate the degree of enrichment achieved and impact on future trials in subjects with early motor PD. The presence of reduced striatal DAT binding based on visual reads of single photon emission tomography (SPECT) scans in early motor PD subjects was an independent predictor of faster decline in UPDRS Parts II and III as compared to subjects with scans without evidence of dopaminergic deficit (SWEDD) over 24 months. The EMA issued in 2018 a full Qualification Opinion for the use of DAT as an enrichment biomarker in PD trials targeting subjects with early motor symptoms. Exclusion of SWEDD subjects in future clinical trials targeting early motor PD subjects aims to enrich clinical trial populations with idiopathic PD patients, improve statistical power, and exclude subjects who are unlikely to progress clinically from being exposed to novel test therapeutics.

[1]  J. Cedarbaum,et al.  Targeted Therapies for Parkinson's Disease: From Genetics to the Clinic , 2018, Movement disorders : official journal of the Movement Disorder Society.

[2]  Martha Brumfield,et al.  Coalition Against Major Diseases/European Medicines Agency biomarker qualification of hippocampal volume for enrichment of clinical trials in predementia stages of Alzheimer's disease , 2014, Alzheimer's & Dementia.

[3]  Dieter Deforce,et al.  The European Medicines Agency experience with biomarker qualification. , 2015, Methods in molecular biology.

[4]  David J. Brooks,et al.  Molecular imaging of dopamine transporters , 2016, Ageing Research Reviews.

[5]  Chris Leptak,et al.  What evidence do we need for biomarker qualification? , 2017, Science Translational Medicine.

[6]  W. Oertel,et al.  Accurate differentiation of parkinsonism and essential tremor using visual assessment of [123I]-FP-CIT SPECT imaging: the [123I]-FP-CIT study group. , 2000, Movement disorders : official journal of the Movement Disorder Society.

[7]  O. Hornykiewicz Biochemical aspects of Parkinson's disease , 1998, Neurology.

[8]  G. Rizzo,et al.  Accuracy of clinical diagnosis of Parkinson disease , 2016, Neurology.

[9]  S. Amur,et al.  Biomarker Qualification: Toward a Multiple Stakeholder Framework for Biomarker Development, Regulatory Acceptance, and Utilization , 2015, Clinical pharmacology and therapeutics.

[10]  D. Jennings,et al.  Single-photon emission tomography and dopamine transporter imaging in Parkinson's disease. , 2003, Advances in neurology.

[11]  P B Hoffer,et al.  SPECT imaging of dopamine transporters in human brain with iodine-123-fluoroalkyl analogs of beta-CIT. , 1996, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[12]  H. Shill,et al.  Low clinical diagnostic accuracy of early vs advanced Parkinson disease , 2014, Neurology.

[13]  L. Pani,et al.  The European Medicines Agency's strategies to meet the challenges of Alzheimer disease , 2015, Nature Reviews Drug Discovery.

[14]  Koen Van Laere,et al.  EANM procedure guidelines for brain neurotransmission SPECT using 123I-labelled dopamine transporter ligands, version 2 , 2010, European Journal of Nuclear Medicine and Molecular Imaging.

[15]  David J. Brooks,et al.  Imaging biomarkers in Parkinson's disease , 2011, Progress in Neurobiology.

[16]  John Seibyl,et al.  SNM Practice Guideline for Dopamine Transporter Imaging with 123I-Ioflupane SPECT 1.0* , 2012, The Journal of Nuclear Medicine.

[17]  Katie Kingwell Zeroing in on neurodegenerative α-synuclein , 2017, Nature Reviews Drug Discovery.

[18]  A. Singleton,et al.  Finding useful biomarkers for Parkinson’s disease , 2018, Science Translational Medicine.

[19]  J. Seibyl,et al.  The role of the core imaging laboratory in multicenter trials. , 2010, Seminars in nuclear medicine.

[20]  J. Seibyl,et al.  123I‐FP‐CIT SPECT [(123) I‐2β‐carbomethoxy‐3β‐(4‐iodophenyl)‐N‐(3‐fluoropropyl) nortropane single photon emission computed tomography] Imaging in a p.A53T α‐synuclein Parkinson's disease cohort versus Parkinson's disease , 2018, Movement disorders : official journal of the Movement Disorder Society.

[21]  CNS biomarkers: Potential from a regulatory perspective Case study – Focus in low hippocampus volume as a biomarker measured by MRI , 2015, European Neuropsychopharmacology.

[22]  K. Kieburtz,et al.  New drugs for Parkinson's disease: The regulatory and clinical development pathways in the United States , 2018, Movement disorders : official journal of the Movement Disorder Society.

[23]  Claude Nahmias,et al.  Slower progression of Parkinson's disease with ropinirole versus levodopa: The REAL‐PET study , 2003, Annals of neurology.

[24]  B. Bloem,et al.  The Emerging Evidence of the Parkinson Pandemic , 2018, Journal of Parkinson's disease.

[25]  Ian A. Watson,et al.  Dopamine Transporter Neuroimaging as an Enrichment Biomarker in Early Parkinson's Disease Clinical Trials: A Disease Progression Modeling Analysis , 2017, Clinical and translational science.

[26]  C. Tanner,et al.  Biomarker‐driven phenotyping in Parkinson's disease: A translational missing link in disease‐modifying clinical trials , 2017, Movement disorders : official journal of the Movement Disorder Society.

[27]  W. Rocca The burden of Parkinson's disease: a worldwide perspective , 2018, The Lancet Neurology.

[28]  Thomas Meitinger,et al.  Mutations in LRRK2 Cause Autosomal-Dominant Parkinsonism with Pleomorphic Pathology , 2004, Neuron.

[29]  Alberto J Espay,et al.  Disease Modification in Parkinson's Disease: Current Approaches, Challenges, and Future Considerations , 2018, Movement disorders : official journal of the Movement Disorder Society.

[30]  J. Seibyl,et al.  Molecular Imaging Insights into Neurodegeneration: Focus on α-Synuclein Radiotracers , 2014, The Journal of Nuclear Medicine.

[31]  Eugene M. Johnson,et al.  MIXED LINEAGE KINASE INHIBITOR CEP- 1347 FAILS TO DELAY DISABILITY IN EARLY PARKINSON DISEASE , 2008, Neurology.

[32]  A Randomized Controlled Trial Comparing Pramipexole with Levodopa in Early Parkinson's Disease: Design and Methods of the CALM-PD Study , 2000 .

[33]  M. Frasier,et al.  α-synuclein imaging: a critical need for Parkinson's disease research. , 2013, Journal of Parkinson's disease.

[34]  S Fahn,et al.  Parkinson disease, the effect of levodopa, and the ELLDOPA trial. Earlier vs Later L-DOPA. , 1999, Archives of neurology.

[35]  A. Stoessl Challenges and unfulfilled promises in Parkinson's disease , 2017, The Lancet Neurology.

[36]  C. Adler,et al.  Importance of low diagnostic Accuracy for early Parkinson's disease , 2018, Movement disorders : official journal of the Movement Disorder Society.

[37]  C. Tanner,et al.  Dopamine transporter imaging is associated with long‐term outcomes in Parkinson's disease , 2012, Movement disorders : official journal of the Movement Disorder Society.

[38]  A. Lang,et al.  Longitudinal follow-up of SWEDD subjects in the PRECEPT Study , 2014, Neurology.

[39]  D. Jennings,et al.  Conversion to Parkinson Disease in the PARS Hyposmic and Dopamine Transporter–Deficit Prodromal Cohort , 2017, JAMA neurology.

[40]  C. Adler,et al.  Disease duration and the integrity of the nigrostriatal system in Parkinson's disease. , 2013, Brain : a journal of neurology.

[41]  D. Turnbull,et al.  Ageing and Parkinson's disease: Why is advancing age the biggest risk factor?☆ , 2014, Ageing Research Reviews.

[42]  A. Singleton,et al.  The Parkinson Progression Marker Initiative (PPMI) , 2011, Progress in Neurobiology.

[43]  J. Cedarbaum Elephants, Parkinson's Disease, and Proof‐of‐Concept Clinical Trials , 2018, Movement disorders : official journal of the Movement Disorder Society.

[44]  D. Hill,et al.  Molecular Neuroimaging of the Dopamine Transporter as a Patient Enrichment Biomarker for Clinical Trials for Early Parkinson's Disease , 2019, Clinical and translational science.

[45]  Mixed lineage kinase inhibitor CEP-1347 fails to delay disability in early Parkinson disease , 2007, Neurology.

[46]  Arthur W. Toga,et al.  Precompetitive Data Sharing as a Catalyst to Address Unmet Needs in Parkinson’s Disease , 2015, Journal of Parkinson's disease.

[47]  Nin Bajaj,et al.  Clinical utility of dopamine transporter single photon emission CT (DaT-SPECT) with (123I) ioflupane in diagnosis of parkinsonian syndromes , 2013, Journal of Neurology, Neurosurgery & Psychiatry.

[48]  Dopamine transporter brain imaging to assess the effects of pramipexole vs levodopa on Parkinson disease progression. , 2002, JAMA.

[49]  D. Dickson,et al.  Autosomal dominant Parkinson's disease caused by SNCA duplications. , 2016, Parkinsonism & related disorders.

[50]  C. Jack,et al.  NIA-AA Research Framework: Toward a biological definition of Alzheimer’s disease , 2018, Alzheimer's & Dementia.

[51]  W. Westbroek,et al.  Glucocerebrosidase is shaking up the synucleinopathies. , 2014, Brain : a journal of neurology.

[52]  J. Jankovic,et al.  A randomized clinical trial of coenzyme Q10 and GPI-1485 in early Parkinson disease , 2007, Neurology.

[53]  J. Eberling,et al.  A Proposed Roadmap for Parkinson’s Disease Proof of Concept Clinical Trials Investigating Compounds Targeting Alpha-Synuclein , 2018, Journal of Parkinson's disease.

[54]  E. Masliah,et al.  Therapeutic approaches in Parkinson's disease and related disorders , 2016, Journal of neurochemistry.

[55]  Vincenzo Bonifati,et al.  Early-onset parkinsonism caused by alpha-synuclein gene triplication: Clinical and genetic findings in a novel family. , 2015, Parkinsonism & related disorders.

[56]  Susanne A Schneider,et al.  What do patients with scans without evidence of dopaminergic deficit (SWEDD) have? New evidence and continuing controversies , 2015, Journal of Neurology, Neurosurgery & Psychiatry.

[57]  R. Postuma,et al.  Insomnia and somnolence in idiopathic RBD: a prospective cohort study , 2017, npj Parkinson's Disease.